(a) Chromosome instability (CIN), a type of genomic instability that is mitotic error-driven, has a deep impact on carcinogenesis and cancer recurrence. High CIN is a marker for poor prognosis in various cancers, including lung adenocarcinoma. In the tumor genome, CIN can be indicated with Copy Number Alterations (CNA) as its surrogate indicator. Although a diverse array of genes can cause CIN at the cellular level, genes responsible for tumor CNA remain elusive. In this study, we set out to identify genes whose expression shows correlation with CNA in human lung adenocarcinoma.

(b) We employed a novel cross-species in silico analysis. Our previous lung RNAseq results from lung cancer-prone CIN mice indicated 348 misregulated genes (92 up-regulated, 256 down-regulated; 2-fold cutoff, P<0.05). We hypothesized that some of the genes misregulated in CIN mice are involved in genomic instability in tumors. With in silico analysis with a human cancer genome database, we identified five human genes as candidate regulators of CNA in human lung adenocarcinoma: MMP13, NUF2, CCL22, ZNF366, and GPR114. High expression of MMP13, CCL22, ZNF366, and GPR114 was correlated with low CNA, suggesting their role in suppressing CIN. High expression of NUF2 was correlated with high CNA, suggesting its role in increasing CIN.

(c) MMP13 (Matrix Metalloprotease 13) is a protease involved in the breakdown of extracellular matrix. NUF2 (yeast NUF2 Kinetochore Protein homolog) is involved in the mitotic process, the misregulation of which directly leads to CIN. CCL22 (C-C Motif Chemokine Ligand 22), ZNF366 (Zinc Finger Protein 366), and GPR114 (G protein-coupled receptor 114, aka ADGRG5) are generally markers for subsets of immune cells (likely dendritic cells). This result led us to further hypothesize that infiltration of CCL22-, ZNF336-, and/or GPR114-positive immune cells inhibits pre-tumor cells and tumor cells with high CNA.

(d) The removal mechanism of cells with genomic instability is poorly understood. This is the first time that candidate markers for the immune cells directly or indirectly involved in removal of CIN cells have been identified. This study may aid in fine-tuning cancer-preventive immunotherapy that targets lung cells with genomic instability.

Citation Format: Chinthalapally V. Rao, Mudassir Farooqui, Yuting Zhang, Gaurav Kumar, Janani Panneerselvam, Nagendra Yarla, Adam S. Asch, Hiroshi Y. Yamada. Identification of candidate regulators of genomic instability in human lung adenocarcinoma through a new cross-species in silico analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1199.